Abstract
Persistent eosinophil activation in both the upper and lower airway mucosa is a central feature of aspirin-exacerbated respiratory disease (AERD). Eosinophil activation and survival are profoundly influenced by interleukin 5 (IL-5) and its receptor, IL-5R. In patients susceptible to allergic disorders, IL-5 receptor α (IL5RA) polymorphisms have been reported; however, an association with AERD remains unclear. We hypothesize that IL5RA polymorphisms may contribute to eosinophil activation in AERD patients. We recruited 139 AERD patients, 171 aspirin-tolerant asthma patients and 160 normal controls. IL5RA polymorphisms (−5993G>A, −5567C>G and −5091G>A) were genotyped and functional activity of polymorphism was assessed by luciferase reporter assay and electrophoretic mobility shift assay (EMSA). There was no significant difference in the genotype frequency of the three polymorphisms among the three groups. AERD patients carrying the AA genotype at −5993G>A had a significantly higher presence of serum-specific immunoglobulin E (IgE) to staphylococcal enterotoxin A (P=0.008) than those with the GG/GA genotype. In vitro, the −5993A allele had a higher promoter activity compared with the −5993G allele in human mast cell (HMC-1; P=0.030) and human promyelocytic leukemia (HL-60; P=0.013) cells. In EMSA, a −5993A probe produced a specific shifted band than the −5993G had. These findings suggest that a functional polymorphism in IL5RA may contribute to eosinophil and mast cell activation along with specific IgE responses to staphylococcal enterotoxin A in AERD patients.
Highlights
Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in individuals with chronic asthma after exposure to aspirin and most other nonsteroidal anti-inflammatory drugs
In electrophoretic mobility shift assay (EMSA), a À5993A probe produced a specific shifted band than the À5993G had. These findings suggest that a functional polymorphism in IL-5 receptor a (IL5RA) may contribute to eosinophil and mast cell activation along with specific immunoglobulin E (IgE) responses to staphylococcal enterotoxin A in AERD patients
The baseline forced expiratory volume after 1 s (FEV1)% and methacholine PC20, the provocative concentration of methacholine required to cause a 20% fall in FEV1, levels were significantly lower in patients with AERD (Po0.001, respectively), whereas the percentage decrease in FEV1 after aspirin provocation was significantly greater in AERD patients than in ATA patients (Po0.001)
Summary
Aspirin-exacerbated respiratory disease (AERD) refers to the development of bronchoconstriction in individuals with chronic asthma after exposure to aspirin and most other nonsteroidal anti-inflammatory drugs. The IL-5R, a heterodimer consisting of a-subunit (IL5RA on 3p26-p24) and b-subunit, is expressed on eosinophils, basophils and mast cells.[9,10] Single-nucleotide polymorphisms (SNPs) of the IL5RA gene have been documented in asthma and other allergies, and are thought to cause enhanced levels of peripheral blood eosinophils and ECP.[11,12,13] Increased numbers of IL5RA mRNA-positive cells in the bronchial biopsies of asthmatic subjects have been reported.[14] Recent attention has focused on the development of a humanized monoclonal antibody targeting the IL5RA as a therapeutic agent to treat eosinophil-dominant asthma. This works by reducing the level of peripheral blood eosinophils and ECPs in mild asthmatics,[15] demonstrating the critical role of IL5RA in the development of IL-5-mediated eosinophil activation in the inflammation of the upper and lower airways
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